LMX1B missense-perturbation of regulatory element footprints disrupt postnatal serotonergic forebrain axon arborization [ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA1196413 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31667191_1.fastq.gz | Fastqsanger.gz | |||
| SRR31667191_2.fastq.gz | Fastqsanger.gz | |||
| SRR31667192_1.fastq.gz | Fastqsanger.gz | |||
| SRR31667192_2.fastq.gz | Fastqsanger.gz |
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Project description:LMX1B missense-perturbation of regulatory element footprints disrupt postnatal serotonergic forebrain axon arborization
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Project description:Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitotic serotonin (5-HT) neuron development; over two hundred pathogenic heterozygous mutations have been discovered in human LMX1B, yet their impact on brain development has not been investigated. Here, we developed mouse models with different LMX1B DNA-binding missense mutations. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital Genomic Footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains or unchanged accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Lmx1b missense heterozygosity further caused wide disruption of Lmx1b-dependent regulatory networks comprising diverse TFs. These findings suggest Lmx1b missense heterozygosity forces complex dominant negative-like and hypomorphic perturbations on serotonergic regulatory element TF binding and accessibility. Our work illustrates the power of DGF for gaining insight into how TF missense mutations disrupt regulatory networks within neuronal epigenomes.
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Project description:Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitotic serotonin (5-HT) neuron development; over two hundred pathogenic heterozygous mutations have been discovered in human LMX1B, yet their impact on brain development has not been investigated. Here, we developed mouse models with different LMX1B DNA-binding missense mutations. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital Genomic Footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains or unchanged accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Lmx1b missense heterozygosity further caused wide disruption of Lmx1b-dependent regulatory networks comprising diverse TFs. These findings suggest Lmx1b missense heterozygosity forces complex dominant negative-like and hypomorphic perturbations on serotonergic regulatory element TF binding and accessibility. Our work illustrates the power of DGF for gaining insight into how TF missense mutations disrupt regulatory networks within neuronal epigenomes.
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Project description:Pathogenic coding mutations are prevalent in human neuronal transcription factors (TFs) but how they disrupt development is poorly understood. Lmx1b is a master transcriptional regulator of postmitotic serotonin (5-HT) neuron development; over two hundred pathogenic heterozygous mutations have been discovered in human LMX1B, yet their impact on brain development has not been investigated. Here, we developed mouse models with different LMX1B DNA-binding missense mutations. Missense heterozygosity effected highly specific deficits in the postnatal maturation of forebrain serotonin axon arbors, primarily in the hippocampus and motor cortex, which was associated with spatial memory defects. Digital Genomic Footprinting (DGF) revealed that missense heterozygosity caused complete loss of Lmx1b motif protection and chromatin accessibility at sites enriched for a distal active enhancer/active promoter histone signature and homeodomain binding motifs; at other bound Lmx1b motifs, varying levels of losses, gains or unchanged accessibility were found. The spectrum of footprint changes was strongly associated with synapse and axon genes. Lmx1b missense heterozygosity further caused wide disruption of Lmx1b-dependent regulatory networks comprising diverse TFs. These findings suggest Lmx1b missense heterozygosity forces complex dominant negative-like and hypomorphic perturbations on serotonergic regulatory element TF binding and accessibility. Our work illustrates the power of DGF for gaining insight into how TF missense mutations disrupt regulatory networks within neuronal epigenomes.
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Project description:LMX1B missense-perturbation of regulatory element footprints disrupt postnatal serotonergic forebrain axon arborization [ATAC-seq]
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Project description:Formation of long-range axons occurs over multiple stages of morphological maturation. However, the intrinsic transcriptional mechanisms that temporally control different stages of axon projection development are unknown. Here, we addressed this question by studying the formation of mouse serotonin (5-HT) axons, the exemplar of long-range profusely arborized axon architectures. We report that LIM homeodomain factor 1b (Lmx1b)-deficient 5-HT neurons fail to generate axonal projections to the forebrain and spinal cord. Stage-specific targeting demonstrates that Lmx1b is required at successive stages to control 5-HT axon primary outgrowth, selective routing, and terminal arborization. We show a Lmx1b→Pet1 regulatory cascade is temporally required for 5-HT arborization and upregulation of the 5-HT axon arborization gene, Protocadherin-alphac2, during postnatal development of forebrain 5-HT axons. Our findings identify a temporal regulatory mechanism in which a single continuously expressed transcription factor functions at successive stages to orchestrate the progressive development of long-range axon architectures enabling expansive neuromodulation.
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Project description:Lmx1b is required at multiple stages to build expansive serotonergic axon architectures
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Project description:Neurons must function for decades of life but how these non-dividing cells are preserved is poorly understood. Using mouse serotonin (5-HT) neurons as a model, we discovered a novel adult-stage transcriptional program specialized to ensure the preservation of serotonergic connectivity. We uncover a switch in Lmx1b and Pet1 transcription factor function from controlling embryonic axonal growth to sustaining a transcriptomic signature of serotonergic connectivity comprising functionally diverse synaptic and axonal genes. Adult-stage deficiency of Lmx1b and Pet1 caused slowly progressive degeneration of 5-HT synapses and axons, increased susceptibility of 5-HT axons to neurotoxic injury, and abnormal stress responses. Axon degeneration occurred in a die back pattern and was accompanied by accumulation of alpha-synuclein and APP in spheroids and mitochondrial fragmentation without cell body loss. Our findings suggest neuronal connectivity is transcriptionally protected by maintenance of connectivity transcriptomes; progressive decay of such transcriptomes may contribute to age-related diseases of brain circuitry.
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Project description:Neuronal programming by forced expression of transcription factors (TFs) holds promise for clinical applications of regenerative medicine. However, the mechanisms by which TFs coordinate their activities on the genome and control distinct neuronal fates remain obscure. Using direct neuronal programming of embryonic stem cells, we dissected the contribution of a series of TFs to specific neuronal regulatory programs. We deconstructed the Ascl1-Lmx1b-Foxa2-Pet1 TF combination that has been shown to generate serotonergic neurons and found that stepwise addition of TFs to Ascl1 canalizes the neuronal fate into a diffuse monoaminergic fate. The addition of pioneer factor Foxa2 represses Phox2b to induce serotonergic fate, similar to in vivo regulatory networks. Foxa2 and Pet1 appear to act synergistically to upregulate serotonergic fate. Foxa2 and Pet1 co-bind to a small fraction of genomic regions but mostly bind to different regulatory sites. In contrast to the combinatorial binding activities of other programming TFs, Pet1 does not strictly follow the Foxa2 pioneer. These findings highlight the challenges in formulating generalizable rules for describing the behavior of TF combinations that program distinct neuronal subtypes.
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